scholarly journals Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Iain W. McNae ◽  
James Kinkead ◽  
Divya Malik ◽  
Li-Hsuan Yen ◽  
Martin K. Walker ◽  
...  
Keyword(s):  
Drug Targets ◽  
Active Sites ◽  
Human African Trypanosomiasis ◽  
Tsetse Fly ◽  
African Trypanosomiasis ◽  
Allosteric Inhibitors ◽  
Parasitic Protist ◽  
Species Specific ◽  
Allosteric Mechanisms ◽  
Stage 1

AbstractThe parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.

Human African trypanosomiasis

2020 ◽  
pp. 1451-1459
Author(s):  
Reto Brun ◽  
Johannes Blum
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Specific Treatment ◽  
Protozoan Parasite ◽  
Control Measures ◽  
Tsetse Flies ◽  
African Trypanosomiasis ◽  
Control Programmes ◽  
The 1960S ◽  
Stage 1

Human African trypanosomiasis (sleeping sickness) is caused by subspecies of the protozoan parasite Trypanosoma brucei. The disease is restricted to tropical Africa where it is transmitted by the bite of infected tsetse flies (Glossina spp.). Control programmes in the 1960s were very effective, but subsequent relaxation of control measures led to recurrence of epidemic proportions in the 1980s and 1990s. Control is now being regained. Untreated human African trypanosomiasis is almost invariably fatal. Specific treatment depends on the trypanosome subspecies and the stage of the disease. Drugs used for stage 1 include pentamidine and suramin, and for stage 2 include melarsoprol, eflornithine, and nifurtimox, but regimens are not standardized, and treatment is difficult and dangerous; all of the drugs used have many side effects, some potentially lethal.

In silico analysis of proteins and microRNAs related to human African trypanosomiasis in tsetse fly

2020 ◽  
Vol 88 ◽  
pp. 107347
Author(s):  
Zhiyuan Yang ◽  
Mingqiang Wang ◽  
Xi Zeng ◽  
Angel Tsz-Yau Wan ◽  
Stephen Kwok-Wing Tsui
Keyword(s):  
In Silico ◽  
Human African Trypanosomiasis ◽  
In Silico Analysis ◽  
Tsetse Fly ◽  
African Trypanosomiasis ◽  
Silico Analysis

scholarly journals New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

2020 ◽  
Vol 5 (1) ◽  
pp. 29 ◽  
Author(s):  
Emily A. Dickie ◽  
Federica Giordani ◽  
Matthew K. Gould ◽  
Pascal Mäser ◽  
Christian Burri ◽  
...  
Keyword(s):  
Oral Therapy ◽  
Human African Trypanosomiasis ◽  
First Century ◽  
New Drugs ◽  
World Health ◽  
African Trypanosomiasis ◽  
Twenty First Century ◽  
Health Organization ◽  
Stage 1 ◽  
Competing Priorities

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

scholarly journals A Tale of Three Species: Adaptation ofSodalis glossinidiusto Tsetse Biology,WigglesworthiaMetabolism, and Host Diet

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rebecca J. Hall ◽  
Lindsey A. Flanagan ◽  
Michael J. Bottery ◽  
Vicki Springthorpe ◽  
Stephen Thorpe ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Strong Dependence ◽  
Tsetse Fly ◽  
Disease Spread ◽  
Growth Media ◽  
Insect Vector ◽  
African Trypanosomiasis ◽  
Content Type ◽  
Sodalis Glossinidius

ABSTRACTThe tsetse fly is the insect vector for theTrypanosoma bruceiparasite, the causative agent of human African trypanosomiasis. The colonization and spread of the trypanosome correlate positively with the presence of a secondary symbiotic bacterium,Sodalis glossinidius. The metabolic requirements and interactions of the bacterium with its host are poorly understood, and herein we describe a metabolic model ofS. glossinidiusmetabolism. The model enabled the design and experimental verification of a defined medium that supportsS. glossinidiusgrowthex vivo. This has been used subsequently to analyzein vitroaspects ofS. glossinidiusmetabolism, revealing multiple unique adaptations of the symbiont to its environment. Continued dependence on a sugar, and the importance of the chitin monomerN-acetyl-d-glucosamine as a carbon and energy source, suggests adaptation to host-derived molecules. Adaptation to the amino acid-rich blood diet is revealed by a strong dependence onl-glutamate as a source of carbon and nitrogen and by the ability to rescue a predictedl-arginine auxotrophy. Finally, the selective loss of thiamine biosynthesis, a vitamin provided to the host by the primary symbiontWigglesworthia glossinidia, reveals an intersymbiont dependence. The reductive evolution ofS. glossinidiusto exploit environmentally derived metabolites has resulted in multiple weaknesses in the metabolic network. These weaknesses may become targets for reagents that inhibitS. glossinidiusgrowth and aid the reduction of trypanosomal transmission.IMPORTANCEHuman African trypanosomiasis is caused by theTrypanosoma bruceiparasite. The tsetse fly vector is of interest for its potential to prevent disease spread, as it is essential forT. bruceilife cycle progression and transmission. The tsetse’s mutualistic endosymbiontSodalis glossinidiushas a link to trypanosome establishment, providing a disease control target. Here, we describe a new, experimentally verified model ofS. glossinidiusmetabolism. This model has enabled the development of a defined growth medium that was used successfully to test aspects ofS. glossinidiusmetabolism. We presentS. glossinidiusas uniquely adapted to life in the tsetse, through its reliance on the blood diet and host-derived sugars. Additionally,S. glossinidiushas adapted to the tsetse’s obligate symbiontWigglesworthia glossinidiaby scavenging a vitamin it produces for the insect. This work highlights the use of metabolic modeling to design defined growth media for symbiotic bacteria and may provide novel inhibitory targets to block trypanosome transmission.

scholarly journals Structures of pyruvate kinases display evolutionarily divergent allosteric strategies

2014 ◽  
Vol 1 (1) ◽  
pp. 140120 ◽  
Author(s):  
Hugh P. Morgan ◽  
Wenhe Zhong ◽  
Iain W. McNae ◽  
Paul A. M. Michels ◽  
Linda A. Fothergill-Gilmore ◽  
...  
Keyword(s):  
Active Sites ◽  
Salt Bridges ◽  
Structural Comparison ◽  
Underlying Principle ◽  
Specificity Constant ◽  
Rocking Motion ◽  
Species Specific ◽  
Allosteric Mechanisms ◽  
Pyruvate Kinases ◽  
T State

The transition between the inactive T-state (apoenzyme) and active R-state (effector bound enzyme) of Trypanosoma cruzi pyruvate kinase (PYK) is accompanied by a symmetrical 8° rigid body rocking motion of the A- and C-domain cores in each of the four subunits, coupled with the formation of additional salt bridges across two of the four subunit interfaces. These salt bridges provide increased tetramer stability correlated with an enhanced specificity constant ( k cat / S 0.5 ). A detailed kinetic and structural comparison between the potential drug target PYKs from the pathogenic protists T. cruzi , T. brucei and Leishmania mexicana shows that their allosteric mechanism is conserved. By contrast, a structural comparison of trypanosomatid PYKs with the evolutionarily divergent PYKs of humans and of bacteria shows that they have adopted different allosteric strategies. The underlying principle in each case is to maximize ( k cat / S 0.5 ) by stabilizing and rigidifying the tetramer in an active R-state conformation. However, bacterial and mammalian PYKs have evolved alternative ways of locking the tetramers together. In contrast to the divergent allosteric mechanisms, the PYK active sites are highly conserved across species. Selective disruption of the varied allosteric mechanisms may therefore provide a useful approach for the design of species-specific inhibitors.

scholarly journals Livestock, pathogens, vectors, and their environment: a causal inference-based approach to estimating the pathway-specific effect of livestock on human African trypanosomiasis risk

2022 ◽  
Author(s):  
Julianne Meisner ◽  
Agapitus Kato ◽  
Marshall Lemerani ◽  
Erick Mwamba Miaka ◽  
Acaga Ismail Taban ◽  
...  
Keyword(s):  
Environmental Change ◽  
Causal Inference ◽  
Disease Transmission ◽  
Human African Trypanosomiasis ◽  
Spatial Epidemiology ◽  
Specific Effect ◽  
Tsetse Fly ◽  
Tsetse Flies ◽  
African Trypanosomiasis ◽  
Change Effect

Livestock are important reservoirs for many diseases, and investigation of such zoonoses has long been the focus of One Health research. However, the effects of livestock on human and environmental health extend well beyond direct disease transmission.  In this retrospective ecological cohort study we use pre-existing data and methods derived from causal inference and spatial epidemiology to estimate three hypothesized mechanisms by which livestock can come to bear on human African trypanosomiasis (HAT) risk: the reservoir effect, by which infected cattle and pigs are a source of infection to humans; the zooprophylactic effect, by which preference for livestock hosts exhibited by the tsetse fly vector of HAT means that their presence protects humans from infection; and the environmental change effect, by which livestock keeping activities modify the environment in such a way that habitat suitability for tsetse flies, and in turn human infection risk, is reduced. We conducted this study in four high burden countries: at the point level in Uganda, Malawi, and Democratic Republic of Congo (DRC), and at the county-level in South Sudan. Our results indicate cattle and pigs play an important reservoir role for the rhodesiense form (rHAT) in Uganda, however zooprophylaxis outweighs this effect for rHAT in Malawi. For the gambiense form (gHAT) we found evidence that pigs may be a competent reservoir, however dominance of the reservoir versus zooprophylactic pathway for cattle varied across countries. We did not find compelling evidence of an environmental change effect.

scholarly journals Tsetse Flies (Glossina) as Vectors of Human African Trypanosomiasis: A Review

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Florence Njeri Wamwiri ◽  
Robert Emojong Changasi
Keyword(s):  
Disease Transmission ◽  
Human African Trypanosomiasis ◽  
Tsetse Fly ◽  
Public Health Issue ◽  
Tsetse Flies ◽  
African Trypanosomiasis ◽  
Land Use Patterns ◽  
Transmission Cycle ◽  
Use Patterns ◽  
Abundance And Distribution

Human African Trypanosomiasis (HAT) transmitted by the tsetse fly continues to be a public health issue, despite more than a century of research. There are two types of the disease, the chronicgambienseand the acuterhodesiense-HAT. Fly abundance and distribution have been affected by changes in land-use patterns and climate. However, disease transmission still continues. Here, we review some aspects of HAT ecoepidemiology in the context of altered infestation patterns and maintenance of the transmission cycle as well as emerging options in disease and vector control.

scholarly journals Modelling the impact of fexinidazole use on human African trypanosomiasis (HAT) transmission in the Democratic Republic of the Congo

2021 ◽  
Vol 15 (11) ◽  
pp. e0009992
Author(s):  
Aatreyee M. Das ◽  
Nakul Chitnis ◽  
Christian Burri ◽  
Daniel H. Paris ◽  
Swati Patel ◽  
...  
Keyword(s):  
Hospital Admission ◽  
Lumbar Puncture ◽  
Human African Trypanosomiasis ◽  
Democratic Republic ◽  
Oral Treatment ◽  
World Health ◽  
Disease Stage ◽  
African Trypanosomiasis ◽  
Republic Of The Congo ◽  
Stage 1

Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to care.

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